Project Summary Epstein-Barr virus (EBV) is a gammaherpesvirus that causes infectious mononucleosis and is associated with B cell and epithelial cell cancers. EBV is an enveloped virus and therefore requires the fusion of the viral and cellular membrane to infect cells. The specificity of cell infection and membrane fusion triggered by the virus is for B cell entry is governed by four viral glycoproteins (gH, gL, gB and gp42), whereas EBV entry into epithelial cells requires three viral glycoproteins (gH, gL, and gB). The gB protein is thought to play the primary role in mediating membrane fusion, receiving activating signals from the other proteins after receptor binding to cells. The gH and gL proteins form a complex that also associates with gp42, and this three-way complex is necessary for binding receptors on B cells and triggering their infection. However, for epithelial cells, gHgL interacts directly with EphA2 triggering EBV membrane fusion and entry, presumably by activating gB. These triggering complexes of gHgL and cellular receptors are critically important for initiating EBV infection, but little is known about their structure and mechanism of action. In this proposal, the Jardetzky, Longnecker, and Zhou research groups will collaborate on studies of the architecture and mechanism of EBV epithelial cell triggering complexes, to gain greater insight into herpesvirus entry into cells. These studies may reveal general features of herpesvirus-mediated membrane fusion and open new possibilities for antiviral or vaccine development.